Skip to main content

Full text of "Croonian Lecture, 1906: On Nerve Endings and on Special Excitable Substances in Cells"

See other formats


170 



Ckoonian Lecture, 1906. — On Nerve Endings and on Special 

Excitable Substances in Cells. 

By J. N". Langley, F.R.S., Professor of Physiology in the University of 

Cambridge. 

(Received and Read May 24, 1906.) 

Amongst the fundamental problems of physiology is the determination 
of the actual seat of the changes which accompany or are the cause of 
physiological activity. The earliest step was the attribution of the more 
obvious functions of the body to the several organs which compose it. This 
has been followed by more or less successful attempts to ascertain the 
separate function of each tissue of an organ, and of each constituent of 
a tissue. And in recent years investigation has been largely concerned with 
the endeavour to localise functions long known, and those which from time 
to time are discovered, in the several parts, and in the several chemical 
constitutents of the ultimate unit, the cell. 

I propose to-day to consider what is the actual seat of certain physiological 
activities in cells, and chiefly in those of muscular and nervous tissues. 
About 50 years ago Claude Bernard investigated the action of various 
poisons on the properties of the nervous and muscular systems. The main 
conclusions which he drew are still almost universally accepted. The most 
important observations were those on the action of curari. It had long been 
known that a muscle contracted when it was stimulated, but it was a 
question of interminable argument whether it responded to the stimulus in 
virtue of its own intrinsic properties, or in consequence of the presence 
of nerve-fibres in its substance. 

Bernard discovered that after a small amount of curari had been adminis- 
tered to a frog, the motor nerves of the muscles of the trunk and limbs were 
no longer capable of causing contraction, but that the muscles contracted in 
the usual manner when stimulated directly. Assuming that the nerve- fibres 
in the muscles were as incapable of causing contraction as those outside 
them, it followed that the muscles are excitable in themselves, apart from 
any nervous impulses, and thus the first piece of fairly satisfactory evidence 
was obtained that muscle is not only contractile but irritable by other 
agencies than its nerves. Bernard* also showed that curari in the amount 

* Pelouze and Bernard (' Comptes Rendus Acad. d. Sci., 5 1850, p. 533) were the first to 
point out that stimulation of the nerves had no effect in a frog to which curari had been 
administered. Bernard continued the investigation of the action of curari, and gave the 



Nerve Endings and Special Excitable Substances in Cells. 171 

required to paralyse the motor nerve* did not paralyse either the sensory 
nerves or the central nervous system, or the trunks of the nerves near the 
central nervous system. He concluded that the primary poisoning effect of 
curari was due to a local action on that part of the nerve which lies in the 
muscle. 

He pointed out also a similar local action on other tissues in the case of 
other poisons. Thus strychnine caused convulsions by an action on the 
central nervous system, but did not appreciably affect the properties of 
nerve-fibres or of muscles. And sulpho-cyanide of potassium destroyed the 
irritability of muscles — so that on stimulating them electrically, or pinching 
them or cutting them, no contraction could be obtained — but it had no 
marked action on either the central nervous system or the nerve-fibres. 

Bernard's experiments thus distinguished a difference of behaviour in the 
nerve trunks, in the branches of the nerves in the muscle, and in the muscle 
itself, as well as (presumably) in the nerve cells of the central nervous 
system. 

On the discovery of the nerve endings in vertebrate muscle, with their 
characteristic appearance in each class of animals, the paralysing action of 
curari on the peripheral branches of the motor nerves was naturally referred 
to the endings, and thus the nerve endings were taken to be different from 
the fibres from which they arose by division, and curari was said to paralyse 
nerve endings. This view was strengthened by the prevailing opinion that 
curari after prolonged action or in sufficiently large doses affected the nerve 
trunks also, for if the nerve endings were specially differentiated parts 
of the nerve-fibres it would be more reasonable to suppose that they would 
be specially affected by curari it the nerve-fibres were affected to some 
extent, however small, than if they were completely unaffected. 

According to Bernard, curari acted first on the " terminations" of the motor nerves, and 
then, if in sufficient amount, gradually robbed the rest of the nerve of its irritability, 
beginning at the periphery and spreading towards the centre. A paralysing action on 
the nerve trunk was also found by Kolliker. Kuhnet observed that in frogs recovering 
from slight curari paralysis the nerve first became effective near its end, and only later 
near its origin from the spinal cord. Later,J however, in experiments on the nerves close 

results in his lectures. Whilst these lectures were in the press (' Lecons sur les Effets des 
Substances Toxiques et Medicamenteuses,' Paris, 1857), and before Bernard's results were 
generally known out of France, Kolliker published the observations he had made on the 
action of curari (cf. ' Virchow's Archiv/ vol. 10, p. 3, 1856). His results agreed in general 
with those of Bernard. 

* The phrase " paralysis of the nerve " is used in its customary sense to indicate that 
on stimulation it does not have its usual effect. 

t Kuhne, 'MuJler's Archiv,' 1860, p. 477. 

J Kuhne, 'Ueber d. Wirkung des Pfeilgiftes auf die Nervenstamme/ Heidelberg, 1880. 

P 2 



172 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

to their endings in the muscles, he did not find that curari in large amount had any effect 
on them, and he was unable to reconcile this with his previous results. In fact, the 
question of the action of curari on nerves before they enter muscle is still one for 
discussion. 

The view of the special character of the nerve endings has been further 
strengthened by histological observations on the changes occurring in the 
nerve endings under the influence of curari. Kuhne described the living 
nerve endings in the muscle of lizards as having more distinct outlines after 
deep curari poisoning, and still more after slight curari poisoning and pro- 
longed electrical stimulation of the nerves.* Miuraf stated that prolonged 
(18 days) curari poisoning in the frog caused a dwindling in the size of 
hypolemmal fibres. Herzen and Odierj find that curari causes the hypo- 
lemmal fibres of the frog to become varicose, and that the axons of the nerve 
outside the muscle became covered with fine granules, the change decreasing 
towards the centre. 

A variant of the general view was early put forward by Kuhne. Kiihne§ 
noticed that the irritability of the parallel -fibred sartorius muscle of the frog- 
was not the same throughout. It was least at the ends, where, as he also 
found, no nerves or nerve endings were present. It was greatest near the 
point of entrance of the nerve. This, of course, might only mean that the 
nerve was more irritable than the muscle. But he found that curari, given 
in amount sufficient to paralyse the motor nerve to the muscle, did not 
abolish the difference in irritability between the middle and the ends of the 
muscle. This he considered could not be due to a difference in the muscle 
itself, since if he passed a constant current through the nerve supplying the 
muscle, the positive pole being near the muscle, so that the end of the nerve 
was thrown into an electrotonus, the irritabilitv of the muscle became the 
same throughout. Consequently, he concluded that the terminal portion of 
the nerve, and possibly the whole nerve ending, was not paralysed by an 
amount of curari considerably greater than that required to block the passage 
of nervous impulses. 

After a very large dose of curari, Kuhne considered that the 
whole nerve ending was paralysed,|| although he obtained inconstant 

* Kiihne, ' Verh. d. Naturhist.-Med. Vereins zu Heidelberg,' N.F., III, 1882. 

f Miura, ' Virchow's Archiv,' vol. 105, p. 129, 1886. 

J Herzen and Odier, 'Arch. Intern, d. Physiol., 5 vol. 1, p. 364, 1904. 

§ Kuhne, ' Mailer's Archiv/ 1860, p. 477. 

|| According to Kiihne, a saturated solution of sugar stimulates nerve but not muscle. 
The solution caused contraction only when applied to those parts of the sartorius muscle 
of the frog which contain nerve-fibres. This action was abolished by sufficiently deep 
poisoning with curari. 



1906.] Special Excitable Substances in Cells. 173 

results as regards the equal irritability of the different regions of the 
muscle.* 

On Kiihne's view, then, curari readily paralysed a part of the nerve in the 
muscle a short distance before its ending ; with an increasing dose of curari, 
the paralysis spread both down and up the nerve-fibres till finally the whole 
was paralysed; the proper irritability and contractility of the muscle 
remaining the same. 

Some years later, Pollitzer,f working in Kiihne's laboratory, confirmed the 
unequal irritability of different parts of the sartorius muscle, and found that 
the irritability corresponded with the number of nerve endings described 
by Mays in the different regions. He supported Kiihne's view that the 
primary action of curari was not on the actual terminations of the nerves, 
and suggested that it might be on the cement substance of the last node, and 
not directly on either nerve ending or axis cylinder. 

The difficulties in understanding the action of curari brought out by the 
work of Kuhne and Pollitzer have had but little influence either on opinion 
or on the course of investigation, and I am uncertain whether Kuhne himself 
adhered to his original view. Almost universally the simple and more 
intelligible theory has been taken that the axis cylinder of a nerve- fibre, 
in branching to make the nerve ending, alters its properties and is more 
susceptible to the action of various poisons. 

A recognition of a difference in the properties of nerve endings and 
nerve-fibres has coloured the interpretation of physiological facts more and 
more as further facts have become known. Thus when the phenomena of 
fatigue were investigated, the nerve endings came to be considered as more 
liable to fatigue than the muscle, and as being different from nerve-fibres 
in which fatigue was produced with difficulty or not at all. The theory has 
also been applied to the connection of nerve-fibres with unstriated muscle* 
with gland cells, and more recently to the connection of nerve cells with 
one another. In all these cases, though to a varying degree, the nerve 
endings are commonly held to be especially affected by numerous poisons 
and as especially liable to fatigue. Lastly, in some cases the phenomena 
observed during the degeneration of a nerve have been attributed to the 
vitality of the nerve ending being greater than that of the axis cylinder 
of the fibre in the nerve trunk. 

■* Sachs ('Keiehert and Du Bois Reymond's Archiv,'* i874, p. 51) stated that, after 
curari in sufficiently lai'ge amount, the irritability of all parts of the muscle became the 
same. Pollitzer (op. cit. infra) found that maximal doses of curari lowered the irritability 
of all parts of the muscle, but that the curve of irritability of the several parts was like 
that of the normal muscle. 

t Pollitzer, ' Journ. of Physiol., 5 vol. 7, p. 274, 1886. 



174 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

JSTow it cannot be denied that the great majority of the known facts receive 
a satisfactory explanation on this theory. Moreover, certain facts — those 
relating to the action of poisons on particular systems of nerves — are not 
easily explained on any other. Nevertheless, some recent observations go 
far to show that the theory is untenable. I will consider first the observa- 
tions on motor nerve endings in striated muscle, since they are at present 
the most complete, and then briefly review those which concern other nerve 
endings. 

Nerve Endings in Striated Muscle. 

Mcotine is one of the many poisons which, in the usual acceptation of the 
phrase, paralyses motor nerve endings in vertebrates. 

In some birds it has an additional action,* not so far observed in mammals. 
It causes certain muscles to pass into a state of tonic rigidity, and to remain 
in this state for many minutes. The contraction is not due to stimuli sent 
out by the central nervous system, for it occurs when all the nerves 
supplying the muscles are severed. If about 1 milligramme of nicotine, or 
any larger quantity, is injected into a vein of an anaesthetised fowl, the hind 
limbs, previously lax, gradually become stiff and extended (of. figs. 1, 2, and 3), 
and they may remain so for a quarter to half an hour, or even longer. 

When a graphic record of the contraction of a single muscle, such as the 
gastrocnemius, is made, the shortening of the muscle is seen to take place 
slowly and steadily to a maximum, which is approximately maintained for 
several minutes ; this is followed by a gradual and much slower relaxation. 




Fig. 1. — Fowl, ansesthetised with morphia and A.C.E. mixture, balanced on its thorax in 
a V-shaped piece of wood. The neck and legs hang down and are flaccid, the 
eyes are shut. 



* Langley, ' Journ. of Physiol.,' vol. 33, p. 380, 1905. 



1906.] 



Special Excitable Substances in Cells. 



175 



lUi^'-H*, 




Fig. 2. — The same fowl as in fig. 1. Two minutes after injection of 5 milligrammes of 
nicotine into the jugular vein. The injection caused a gradual and fairly quick 
extension of the legs, retraction and twisting of the neck, and opening of the 
eyes. In order to show the eyes, the beak was held when taking the photo- 
graph. The fowl was unfastened throughout, and the injection caused no 
general movement nor any decrease of the anaesthesia. 




Fig. 3. — The same fowl half an hour after the injection of 5 milligrammes of nicotine. In 
the interval the fowl had been lifted up to observe the degree of contraction 
of the muscles, so that the position is probably not exactly the same as in the 
previous photograph. Most of the muscles still have some tone, more than 
they have in anesthesia without nicotine ; but the eye muscles are appa- 
rently in the normal ansesthetic state, for the eye is closed. The eye began to 
close in about a quarter of an hour. 

The rate of shortening varies with the amount of nicotine. After intra- 
venous injection of 1 to 5 milligrammes the approximate maximum is not 
attained for 20 to 30 seconds ; and even with very large amounts the rate is 
never comparable with that of the rapid twitch which is obtained by 



176 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

stimulating the nerve with the make or break of a galvanic current, or with 
a single induction shock. The contraction, in fact, is of a peculiar kind, not 
reproducible apparently by electrical stimulation of the nerve. 

As I have already said, it is well known that nicotine has a similar effect 
to curari in so far as it prevents stimulation of a motor nerve from having 
any effect upon the muscle. In the fowl the paralysis is produced by 10 to 
15 milligrammes of nicotine. The stimulating effect of nicotine occurs 
whether the amount given is sufficient to paralyse the motor nerves or no ; 
amounts from about 05 milligramme upwards all cause contraction. 
Moreover, after the nervous effect has been abolished by 10 to 15 milli- 
grammes, a subsequent dose will still cause muscular contraction, and by 
increasing the amount of successive doses contraction can be obtained 
a considerable number of times in succession, though the effect diminishes 
and at length ceases. This in itself is a curious fact,* for though it is 
extremely common for a drug to stimulate first and then paralyse, the 
recognised action of such drugs is to cease to stimulate after the paralysis has 
been produced. 

The hypothesis which first suggests itself to account for this fact is that 
nicotine acts in different ways upon two different parts of the neuro- 
muscular mechanism, paralysing the nerve endings on the one hand, and 
stimulating the muscle on the other. 

It is clear that this view would be confirmed if curari had no effect upon 
the contraction caused by nicotine, for, as we have seen, curari is held to have 
an action on nerve endings but not upon muscle. But experiment shows 
that curari has a marked antagonising action on the contraction produced by 
nicotine; a sufficient dose of curari annuls the contraction produced by a 
small amount of nicotine and diminishes that caused bv a large amount. 
The two poisons as regards muscular contraction are mutually antagonistic, 
though nicotine is the more powerful. This point is of fundamental 
importance, and I give the graphic records taken from one experiment in 
illustration of it. 

Fig. 4 shows the contraction caused in a gastrocnemius muscle of the 
fowlf by 4 milligrammes of nicotine. Whilst the contraction was at its 
height, 50 milligrammes of curari were given. This it will be seen abolished 
or nearly abolished the contraction. 

* Some other alkaloids have a similar action ; thus pilocarpin causes secretion, and 
slows the heart after it has paralysed the post-ganglionic nerves. 

t The fowl was ansesthetised by morphia and A.C.E. mixture. The sciatic nerve was 
cut. The lever attached to the gastrocnemius tendon was weighted with 40 grammes. 
For other details of method, cf. ' Journ. of Physiol.,' vol. 33, pp. 381, 382, 1905. 



1906.] 



Special Excitable Substances in Cells. 



177 




Fig. 4. — Abolition by curari of the contraction in the gastrocnemius muscle of the fow 
caused by nicotine. The lowest line marks intervals of 10 seconds. 

The amount of curari given is two to three times the amount required to 
prevent the sciatic causing contraction of the muscle, nevertheless, the 
injection of 50 milligrammes of nicotine about three and a half minutes 
later caused the strong contraction shown in fig. 5, and this contraction in 
turn was reduced nearly to zero by a further injection of 50 milligrammes 
of curari* (fig. 5). A second injection of 50 milligrammes of nicotine 




30 rags, 
izicotlne 



5C.c. 
salt sol. 



5 O rags. 

cur art- 



Fig. 5.— Continuation of tracing given in fig. 4. Mutual antagonism of nicotine and 
curari. The 5 c.c. of salt solution was injected to show that the injection 
itself did not cause relaxation. Time marked in 10 second intervals. 

10 minutes later was almost without effect, the substance stimulated by 
nicotine being temporarily paralysed, but the muscle readily contracted on 
direct electrical stimulation. 

Experiment, then, with curari does not confirm the obvious view as to the 

* Large amounts of curari are apt to weaken or stop the heart, but control experiments 
show that the nicotine contraction continues unaltered for several minutes after complete 
cessation of the heart beat, and that the curari relaxation occurs when the blood pressure 
is unaffected by the injection. 



178 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

mode of action of nicotine given above. It shows that if nicotine has an 
action on muscle, so also has curari. But some other form of experiment 
is required to decide whether nicotine does, in fact, act upon the muscle 
direct. 

It is clear that what is required is to examine the behaviour of the muscle 
when no nerve endings are present. A means to this end is to cut the nerve 
and allow it time to degenerate. It is known that after section, nerve-fibres 
degenerate up to their point of entry into the muscle fibres and it has been 
almost universally assumed that the nerve endings, which are but the 
terminal branches of the nerve, degenerate also. It is, however, as I have 
already said, not uncommonly believed that the nerve endings degenerate 
more slowly than the nerve-fibres, and some doubt has been expressed as to 
whether they degenerate at all. 

This question must then first be examined. The degeneration of the 
nerve endings after section of the nerve-fibres has been taken so much as a 
matter of course, that there are, so far as 1 know, two papers only published 
on the subject. 

The earlier investigations were made by Sokolow,* on the gastrocnemius 
muscle of the frog. He examined the muscle for nerve endings by the gold 
chloride method, 14, 28, 32 and 44 days after section of the sciatic nerve. 

Fourteen days after section of the sciatic nerve, no change was observable 
in the nerve endings. In the other three cases, good staining of the muscle 
was apparently only obtained in that taken 32 days after section of the 
nerve, but it may perhaps be assumed that the changes described were 
observed, though less satisfactorily, in the other two. According to Sokblow, 
the different nerve endings undergo change at very different rates, so that in 
all cases some normal nerve endings remained. Those which were altered, 
but still visible, showed fine dark stained granules in a basis staining 
less than normal. The alteration was sometimes only at the ends of the 
hypolemmal fibres, and different hypolemmal fibres of the same ending 
showed different degrees of change. 

In other cases, some or all of the hypolemmal fibres had completely 
disappeared. 

In the latter type, the nerve-fibre with fragmented myelin was traced up 
to the muscle and Sokolow states that the absence of the nerve ending was 
not due to imperfect staining. In some instances he describes the spaces left 
by the nerve endings as being filled with a fine deposit of gold. 

Although these observations leave something to be desired, they do, I 
think, show that the nerve ending undergoes first granular degeneration and 

* Sokolow, 'Archives de Physiol.,' 1874, p. 300. 



1906.] Special Excitable Substances in Cells. 179 

then absorption. A point which raises some doubt in my mind is a brief 

* 

statement by Sokolow that in all cases contraction was still obtained by 
stimulating the nerve. It seems unlikely that after nerve section some of 
the nerve-fibres and nerve endings should be normal, whilst others had so far 
degenerated that the nerve endings had completely disappeared, or that the 
conductivity of the nerve should last as long as 44 days. 

The second published work on this subject is by Huber.* His observa- 
tions were made on the interosseus muscles of the rabbit, the posterior tibial 
nerves being crushed to interrupt continuity. The nerve endings were 
stained with methylene blue. On the second day after the nerve crashing, 
some of the hypolemmal fibres showed round or oval thickenings staining 
deeply with methylene blue, these rapidly increased in number, and when 
the great majority were in this state, stimulation of the nerve had no longer 
an effect. At a later stage, up to six days, no staining of the nerve endings 
was obtained, but at times there was a faint staining of the sole. Huber, 
however, lays no great stress on this result, since the staining in the normal 
condition was uncertain. At a still later stage (about 30 to 178 days), 
i.e. } when time was allowed for regeneration, nerve endings were again 
obtained. 

The only gap in these observations is that the intermediate forms between 
the first stage of granular degeneration and absorption are not described. 
They show definitely that in mammals the nerve ending alters rapidly on 
nerve section, losing its normal staining power with methylene blue, and 
it may fairly be inferred that the nerve ending, like the axis cylinder, 
degenerates. 

In order to form an independent opinion on the question, I have made some 
observations on the nerve endings of the frog by the methylene blue method. 
In the sartorius muscle of the frog a considerable number of nerve endings 
can with certainty be shown by methylene blue ; I have not had one failure 
in more than a hundred trials. I have cut on one side, under anaesthetics, the 
branch of the sciatic (n. clescendens communis) which supplies the sartorius 
muscle, and a variable time after the section, killed the frog, taken the 
sartorius muscle of the cut and uncut side and treated them in the same 
way in methylene blue. I find that about three weeks after section of the 
nerve, the nerve endings show deep stained small granules in a faintly 
stained basis, that later the granules became smaller and fewer, and the basis 
barely visible. About six weeks after section, no trace of nerve endings is to 
be seen. A semi-diagrammatic sketch of one of the granular nerve endings 
I give in fie. 6. 

* Huber, 'Amer. Journ. of Physiol.,' vol. 3, p. 339, 1900. 



180 Prof. J. N. Langley. On Nerve Endings and on [May 24 



tmw%wi>w'*vi**i*#m.'»»wwit*wev^ 






■' a '*«««j^r:«„*,^^^,.„ i ^ ...<*' "^ . : r 









«—»»»«» »«»<—«■> ^ n .i«i>ii M» ^ i » T W OTt «<tfaMBto ji » i » w » w .i w iti w aK««gwawg^?*y^-^igaa l ^ytff °a««*«**»**t:«*sswjsfi'Sfc 



Fig. 6. — Nerve ending in sartorius muscle of frog three weeks after nerve section. 
Methylene blue stain. The tint of the several parts of the nerve ending in 
the figure represents roughly the degree of stain, but the tint of the hypo- 
lemmal fibres, and, to a less degree, that of the nuclei, is too deep. 

Lastly, Tuckett has investigated the nerve endings in the flexor profundus 
muscle of the pigeon, by the methylene blue method. He finds that the 
hypolemmal fibres show granular degeneration in two days or less, and that 
after three days they disappear. The details of his work will be published 
shortly. 

As the results of these various observations, we may then, I think, safely 
conclude that after section of a nerve, the nerve endings undergo first 
granular degeneration and then absorption. 

And, if this be granted, it is clear that we can determine whether nicotine 
does or does not act on muscle by administering it a sufficient time after 
a motor nerve has been cut. 

I have examined* the reaction of the gastrocnemius muscle of the 
fowl, 6, 8, 27, 38, and 40 days after section of the external peroneal nerve 
which innervates it. In all cases a contraction was obtained essentially 
similar to the normal nicotine contraction, the only difference apparently 
observed being an increased response to small doses of the poison, indicating 
an increased excitability after denervation, such as has been described in some 
cases of unstriated muscle after nerve section. 

Since the contraction is certainly not decreased, and may be increased, by 
degeneration of the nerve endings, the nicotine contraction must be produced 
by an action on the muscle and not on the nerve endings. 

Passing now to the effect of curari. On the fowl's gastrocnemius muscle, 
after degeneration of the nerves, curari is still capable of reducing the 
nicotine contraction. The only difference is that it is — so far as the 
experiments go — a less powerful antagonist ; a fact probably related to the 
apparent increased excitability to nicotine already mentioned. Curari, then, 
must also have an action on the muscle substance. 

* Op. cit. supra. 



1906.] Special Excitable Substances in Cells. 181 

The mutual antagonism of nicotine and curari on muscle* can only 
satisfactorily be explained by supposing that both combine with the same 
radicle of the muscle, so that nicotine-muscle compounds and curari-muscle 
compounds are formed. Which compound is formed depends upon the mass 
of each poison present and the relative chemical affinities for the muscle 
radicle. 

Since the formation of the nicotine-compound causes contraction, and that of 
the curari-compound does not, it is obvious that the chemical re-arrangements 
set up in the muscle molecule by the combination of one of its radicles are 
different in the two cases. In fact, it seems probable" that a special radicle is 
necessary for the combination with a number of chemical bodies, and that 
the compound formed leads to further change depending upon the nature of 
the compound. 

Having then arrived at the conclusion that both nicotine and curari 
combine with some substance in the muscle, we have to consider whether 
there is any reason to suppose that they combine with some substance in the 
nerve ending also. The only action that can be attributed to them is the 
paralysing action. 

There is, unfortunately, no direct and conclusive evidence either one way or 
the other. But as the ascertained action of the poisons on muscle is 
sufficient to explain their paralysing action, it is unnecessary to resort to the 
assumption of an additional effect on nerve endings. It is a common action of 
drugs first to stimulate and then to paralyse, so that there is plenty of analogy 
for the view that nicotine, after stimulating, paralyses the constituent of the 
muscle on which it acts. 

Curari, as we have seen, decreases the irritability of the muscle to the 
nicotine stimulus, and it is reasonable to suppose that it decreases also the 
irritability of the muscle to stimuli arriving by the nerves. I conclude, then, 
in terms of the theory given above, that the compounds which the poisons 
form with the muscle are less irritable and conductive than the normal 
muscle substance. 

The continuation of the stimulating effect of nicotine after nervous impulses 

** Pal (' Centralb. f. Physiol.,' 1900, p. 255) found that curari nerve-paralysis could be 
more or less completely abolished by physostigmine. The matter was further worked out 
by Bothberger ('Arch. f. d. ges. Physiol.,' vol. 137, p. 117, 1901), who also showed (ibid., 
vol. 92, p. 398, 1902) that several substances, and amongst them nicotine, can, in proper 
conditions, partly restore irritability to motor nerves paralysed by curari. In writing 
my earlier account (op. cit. supra) I was unaware of Rothberger's observations. The 
physiological antagonism in this case is very incomplete, a fact which is in harmony with 
the theory of antagonism of poisons I gave some years ago (' Journ. of Physiol., 5 vol. 1, 
p. 367, 1878). 



182 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

is rendered ineffective, we may explain on the supposition that the nicotine 
muscle compound ceases to be irritable or conductive to nervous stimuli, 
before the maximal combination with nicotine has taken place. The degree 
of combination is essentially a question of the relative chemical affinities of 
the radicle of the muscle substance with other radicles and with nicotine. 

It is true that, as mentioned earlier (p. 172), microscopic changes have 
been described in nerve endings as the result of giving curari, but these 
do not necessarily show a special action on the nerve ending. In the 
instance described by Kuhne, the increase in distinctness in the nerve 
endings of the lizard might equally well be due to an action on the " sole " 
or muscular protoplasmic mass below the nerve ending. And with regard 
to the observations of Herzen and Odier it is to be noted that the granular 
changes found in the nerve endings after curari were also found in the axis 
cylinders a variable distance up the trunk of the nerve, and it is certain 
that the abolition of nerve effect, produced by small and by moderate 
amounts of curari, is independent of any changes in the trunk of the nerve. 

Further, there is no certain histological difference between the nerve - 
fibres before and after branching into nerve endings ; although some 
differences have been described, the general evidence is that the nerve 
endings are simply branches of the axis. 

The probability then, I take it, is that none of the phenomena of nerve 
and muscle stimulation are due to a chemical difference between the axis 
cylinder and the nerve endings, and in that case it follows not only that 
the poisoning phenomena of a large number of drugs are due to changes 
brought about directly in some constituent of the muscle, but also that 
the peripheral fatigue usually attributed to changes in the nerve endings 
is really due to fatigue of a special constituent of the muscle. 

Since neither curari nor nicotine, even in large doses, prevents direct 
stimulation of muscle from causing contraction, it is obvious that the muscle 
substance which combines with nicotine or curari is not identical with the 
substance which contracts. It is convenient to have a term for the specially 
excitable constituent, and I have called it the receptive substance. It 
receives the stimulus and, by transmitting it, causes contraction. 

Beyond this we cannot go' at present with any certainty. I may indicate 
briefly one or two possibilities. 

It is well known that Bottazzi* has given reasons for the theory that 
sarcoplasm is contractile, but that it contracts more slowly than the fibrillar 
material. We might then refer the nicotine contraction to the sarcoplasm, 
and the slowness of the contraction would imply that the fibrillge are not 

* Bottazzi, * Journ. of Physiol.,' vol. 2i, p. I, 1897. 



1906.] Special Excitable Substances in Cells. 183 

stimulated at all by nicotine. Since the contraction caused by a single 
electrical stimulation of the nerve is a quick contraction, it would naturally 
follow that it is due solely to the fibrillae. Thus one or other of the two 
contractile substances would come into action alone. But if the stimulating 
action of nicotine is solely in the sarcoplasm, we should naturally conclude, 
in accordance with the argument given above, that its paralysing action is 
also solely on the sarcoplasm. In this ease we should have to conclude 
that the sarcoplasm normally transmits the stimulus caused by a single 
electrical stimulation of the nerve without itself contracting, but does not 
transmit the stimulus caused by nicotine though it does itself contract. 
This conclusion presents great though perhaps not insuperable difficulties. 

If, in consequence of these difficulties, we take the view that the nicotine 
causes contraction of the fibrillae and not of the sarcoplasm, there are two 
possibilities : the receptive substance may be part of the sarcoplasm, or it 
may be a radicle of the contractile molecule. 

It might be urged in favour of the former view that according to Kuhne 
the nerve ending is in some cases completely separated from the fibrillae by 
sarcoplasm. On the other hand, even if a thin layer of sarcoplasm does 
intervene between nerve and muscle, it does not necessarily follow that it 
takes any essential part in the passage of the stimulus. 

On the latter view it is clear that the contractile molecule must either 
have at least one receptive radicle in addition to that affected by nicotine 
and curari, or it must be capable of direct stimulation. The hypothesis, 
however, demands that the stimuli passing by the nerve cannot affect the 
contractile molecule except by the radicle which combines with nicotine and 
curari. And this seems in its turn to require that the nervous impulse 
should not pass from nerve to muscle by an electric discharge, but by the 
secretion of a special substance at the end of the nerve, a theory suggested 
in the first instance by du Bois Eeymond. 

Lastly it is to be noted that whether the receptive substance is part of the 
sarcoplasm or part of the fibrillae, it remains to determine whether the 
receptive substance is localised in the immediate neighbourhood of the nerve 
ending or exists throughout the length of the muscle fibre. The observations 
of Kuhne and Pollitzer (quoted above) on the different irritability of the 
nerve-containing and nerve-free parts of the muscle afford some evidence for, 
at any rate, unequal distribution, but the main question can, I think, only 
be settled by experiments on the effect of local application of nicotine such as 
I have to mention presently. 

In the preceding statement, the view that curari and a number of other 
poisons act on muscle has been placed in sharp antagonism with the view 



184 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

that they act on nerve endings. But the possibility of an intermediate view 
must be mentioned. There are some observers who consider that nerve and 
muscle are continuous, and it is conceivable that a certain region of the 
junction should belong to both nerve and muscle in the sense that either 
could keep it alive. The special properties attributed to the nerve ending 
might then be attributed to the junctional region, half muscle and half 
nerve. With regard to this, it will be noted that the junctional region, if it 
exists, must be in the muscle, since we have good reason to believe that all 
the visible nerve ending degenerates on section of the nerve. 

In the simplest case, that of the nerve endings of amphibia, the substance 
which has been described as continuous with the endings is clearly the 
sarcoplasm of the muscle, which stretches throughout the muscle fibre, and no 
substance of distinct histological characters which could be regarded as a 
junctional substance is shown by the microscope. 

In the end plate form of nerve ending there is it is true the specially 
modified sarcoplasm which forms the "■ sole." But, as was shown by Kuhne, 
some of the hypolemmal fibres commonly run past the limits of the sole. 

But the theory of continuity seems to me to have the balance of evidence 
decidedly against it. As Kuhne* pointed out in a previous Croonian Lecture, 
the properly stained hypolemmal fibres terminate usually in rounded ends 
sharply marked off from the muscle substance, and every method which 
brings out the nerve endings clearly, brings out this characteristic. The 
outline of a hypolemmal fibre is as distinct at its end as it is in its pre- terminal 
course. In the case of typical nerve endings, it is only when they are viewed 
in all the indistinctness of the fresh specimen, or are made granular by treat- 
ment, that any appearance of continuity is suggested. 

Kuhne has also pointed out that excitation of the muscle substance does not 
cause a stimulus to pass back through the nerve ending, and this might 
reasonably be expected to occur if there were continuity. 

The chief observations in favour of continuity are those on the development 
of the nerves in the embryo.f As I have said elsewhere, if it were shown 
that continuity exists in the early embryonic state, it would not follow that it 
continues to exist in later stages. With differentiation of function, histological 
separation might well take place.f 

* Kuhne, ' Roy. Soc. Proa/ vol. 44, p. 427, 1888. 

t For a critical account of these observations, cf. Kolliker, 'Zeitschr. f. wissensch. 
Zool.,' vol. 82, 1905. 

% Since the above was written, a paper has been published by Pfluger (' Arch, f . d. 
ges. Physiol.,' vol. 1 12, p. 1, 1906), in which he upholds the theory of continuity. It is a 
measure of the need for further investigation that the well-known observations on the 



1906.] 



Special Excitable Substances in Cells. 



185 



The preceding argument has been based chiefly on the fact that nicotine 
excites certain muscles in the fowl, as well as abolishes, when given in 
sufficient amount, the effect of the nerves upon them. 

Now, as mentioned already, nicotine abolishes motor nerve action in all 
vertebrates investigated. It would be very remarkable if the stimulating 
action occurred only in birds. I have not made any systematic investigation 
of the question, but, in thinking about it, I remembered that v. Anrep* had 
described catalepsy of the fore limbs of the frog as being caused by nicotine 
after destruction of the spinal cord and that the phenomenon had been 
confirmed by Dickinson and myselff and additional details given. 

The tonic contraction produced in the muscles of the fore limb of the frog£ 
is clearly similar to, though not identical with, that produced in the gastroc- 
nemius and other muscles of the fowl. Its duration, however, may be much 
greater. The effect is to cause the fore legs to be drawn over the sternum in 
the manner described by early observers, who, however, did not definitely 
attribute it to peripheral stimulation. 

An illustration of the effect of nicotine on the fore limbs is given in fig. 7. 
The brain and spinal cord of a frog were destroyed ; in this state the muscles 
are, of course, flaccid, and the limbs if raised and let go. at once fall. The 
frog was placed on its back with the fore limbs by the side of the body. 
Then a little 1 per cent, nicotine was injected into the abdominal cavity ; this 
caused the assumption of the position shown in fig. 7. 




Fig. 7. — Frog. Killed by destroying the whole of the central nervous system. Con- 
traction of the muscles of the fore limbs caused by nicotine. 

If a graphic record of the movement of the limb is taken, it is seen that the 

tissues of vertebrates which he quotes seem to me, as to many others, without exception 
inconclusive. Of the tissues of invertebrates I have but slight experience. 

* v. Anrep, ' Arch. f. (Anat. u.) Physiol.,' 1879, Supp., pp. 167, 209. 

t Langley and Dickinson, ' Journ. of Physiol./ vol. 11, p. 265, 1890. 

% Most of my experiments were made during the breeding season, when,' it is possible 
that the tendency to tonic contraction is greater. 

VOL. LXXVIII. — B. Q 



186 Prof! J. jST. Langley. On Nerve Endings and on [May 24, 

maximum flexion may not be attained for several minutes. Such a record is 
given in fig. 8. 




JC.C.I/J.C 

nicot'irbt 



Fig. 8. — Frog. Brain and spinal cord destroyed. A thread was tied to the manus and 
connected with an unweighted lever, so that flexion of the arm caused a rise of 
the lever,* 1 c.c. 1 per cent, nicotine injected into the abdominal cavity at the 
time shown by the signal. Time marked in 10 seconds. 

The tonic contraction is not confined to the muscles of the fore limb. If 
dilute nicotine (0*05 per cent.) is injected into the bulbus arteriosus, it is 
seen that all the muscles of the body, except those of the thigh and lower 
leg, become tonically contracted. The duration, strength, and other features 
of the contraction vary in different muscles, and in some instances it is 
accompanied by fibrillar twitching. In the thigh and lower leg muscles 
there is, so far as can be seen with the eye, twitching only, if the nicotine 
is sufficiently dilute. Moreover, if instead of injecting nicotine it is applied 
locally to the muscles (0*05 per cent, solution and upwards) local contraction 
is produced ; thus the numerous extensors and flexors of the. toes of the fore 
and hind limb can be made to contract separately. It may be noted, too, that 
the rate of contraction of the abdominal muscles is considerably quicker 
than that of the flexors of the arm. Different muscles, then, show nearly all 
the possible variations. 

An interesting point is that on applying nicotine to a portion of a muscle 
the tonic contraction occurs in this portion only and does not spread to the rest 
of the muscle. When stronger solutions of nicotine (0*5 to 1 per cent.) are 
used, tonic contraction also takes place in the thigh muscles. On application 
to a portion of a muscle, a local wheal, like the ideo-muscular contraction, is 
formed at the place of application. If the sartorius muscle is cut out and 

* It will be noticed that the flexion takes place in a series of small jerks ; the cause of 
this I have not yet investigated. 



1906.] 



Special Excitable Substances in Cells. 



187 



excess of fluid removed, local contraction at the ends of the muscle where 
no nerves are present is obtained by local application of 1 per cent, nicotine, 
the contraction, however, is less strong than that produced by 1 per cent, 
nicotine to the part of the muscle which does contain nerves. If this con- 
traction is a genuine nicotine contraction like that produced in other muscles 
by injection into the circulation of small amounts of nicotine, it shows that 
the nicotine-receptive substance is not confined to the nerve endings. But 
further experiments are required before it can be said that these similar 
contractions are identical * 

I have not had time to make more than a few experiments on the effect of 
curari on the nicotine contraction. So far it results that nicotine will still 
cause contraction after the nerves have been paralysed by curari, but that 
a much larger amount of nicotine is required. Whilst there is a mutual 
antagonism between the two poisons, curari is a much more potent antagonist 
of nicotine than it is in the fowl. 

Mcotine has a similar action on the muscles of the toad, and there is 
a similar mutual antagonism between the action of nicotine and curari on the 
muscles. In the toad the contraction of the flexors and extensors of the 
arm is equal or nearly equal, so that there is little or no movement. f But 
the cataleptic condition is usually much more marked than in the frog, and 
affects the leg as well as the arm, though to a less extent. The fore limbs 
can be moved about almost as if made of lead, and stay with but slight 
return movement in any position in which they are placed consistent with 
the arrangement of the joints and ligaments. In fig. 9 I give a photograph 




Fig. 9. 



of a toad in which the brain and spinal cord had been destroyed, and 
1 per cent, nicotine then injected into the abdominal cavity. The limbs soon 
became cataleptic, and the photograph is taken of one of the positions in 

* Nicotine is strongly alkaline, and I have not yet tried the effect of alkalies. Strong 
curarisation does not abolish the action of 1 per cent, nicotine ; but this may be due to 
the nicotine being in sufficient amount to overcome a curari effect. 

t I have not tried the effect of nicotine on the male toad during the breeding season. 

Q 2 



188 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

which the limbs were placed. It; is noteworthy that this cataleptic condition 
is abolished by a sufficient dose of curari. 

Nerve Endings in Nerve Cells, 

Evidence of a similar nature to that which I have given for the relation 
of motor nerves to striated muscle exists also for the relation of the nerve- 
fibres which run from the spinal cord (pre-ganglionic fibres) to end in con- 
nection with sympathetic nerve cells. 

The action of nicotine on sympathetic nerve cells* is very similar to that 
which it has on the gastrocnemius muscle of the fowl. It stimulates nearly 
all the sympathetic nerve cells of the body, and in larger dose, varying in 
different cases, it abolishes the effect of stimulating the pre-ganglionic 
nerves, i.e., it paralyses the nerve-fibres. 

Curari in large amounts paralyses the pre-ganglionic fibres, the amount 
required varying with different classes of sympathetic fibres ; when it does 
this it prevents a normally effective amount of nicotine from causing any 
stimulation. 

Now nicotine has as strong a stimulating effect on the sympathetic 
ganglia after degeneration of the pre-ganglionic fibres as it has normally. 
There is no suggestion of the existence of any structure in connection 
with the nerve endings which could keep them intact after section of the 
nerves from which they arise, and I conclude that they degenerate after 
nerve section. 

Ram6n y Cajal, Dogiel, Huber, and others, who have used either Golgi's method or 
Ehrlich's methylene blue method for staining nerve endings, find that the nerve-fibres 
running to a sympathetic ganglion are not continuous with the nerve cells, but end free 
in close contact with them. I have obtained similar results by the methylene blue 
method. Anderson (' Journ. of Physiol.,' vol. 28, p. 499, 1902) gives one piece of experi- 
mental evidence for continuity. He finds that in very young animals delay of develop- 
ment of myelin in the cervical sympathetic nerve-fibres occurs not only on section of the 
nerve itself, but also on section of the post -ganglionic fibres of the superior cervical 
ganglion. The latter fact, he considers, shows continuity through the nerve cells of pre- 
and post-ganglionic fibres. It is certain, however, that developing nerve-fibres are much 
more influenced by injuries than the fully formed ones ; and it is possible that the 
atrophy of the nerve cells caused by cutting the post-ganglionic fibres in very young 
animals injures the nerve endings in close contact with them, and in this case the section 
of the post-ganglionic fibres is practically equivalent to section of the pre-ganglionic 
fibres. 

Some evidence against continuity is given by the fact that nicotine applied to a 
ganglion causes no axon reflex ; i.e., the stimulus set up in the nerve cells does not pass 
back to the nerve-fibres. How much weight is to be attached to this depends upon the 
nature of the nervous impulse about which at present there is doubt. But the fact is, I 



* Of. Langley, i Journ. of Physiol./ vol. 27, p. 224, 1901. 



1906.] Special Excitable Substances in Cells. , 189 

think, fairly conclusive against the continuity theory put forward by Bethe ;* for if 
conducting neuro-fibrils traversed the nerve cell, stimulation of the neuro-fibrils in the 
cell either directly or indirectly must lead to nervous impulses being conducted in both 
directions. And that the pre-gauglionic fibres can conduct in both directions is shown by 
the axon reflex produced on electrical stimulation of the nerves. 

Nicotine, then, stimulates the nerve cells. Since curari in sufficient 
amount prevents this action, curari also must act upon nerve cells, and we 
may infer, as in the case of striated muscle, that neither act upon the nerve 
endings. 

It may be noted that there is histological confirmation of the direct 
action of nicotine on nerve cells, for, according to Cosmettatosf it produces 
chromatolysis of the cells of the superior cervical ganglia of the rabbit, 
a change which Eve J showed is not produced by protracted stimulation of 
the cervical sympathetic. 

One piece of evidence is lacking in the case of nerve cells, viz., that they 
retain their fundamental properties after nicotine or curari poisoning in the 
way striated muscle does. The nerve cells cannot be stimulated apart from 
the nerve-fibres these give off, so that it is only by analogy that I conclude 
that the substance affected by the poisons is a special receptive substance 
and not the fundamental substance of the cell. 

The experiments on sympathetic ganglia give, I think, good ground for 
believing that in the central nervous system also, both the specific effect of 
nicotine, strychnine, and other poisons, and the phenomena of fatigue must 
be attributed to an action on nerve cells (either root cells or short fibred 
commissural cells) and not to an action on nerve endings. They support the 
view that the special functions of the central nervous system are carried on 
in vertebrates by the nerve cells (including their dendrons), and not by 
a neuro-fibrillar network outside the nerve cells. 

Nerve Endings in Unstriated Muscle and Glands. 

The nerves under this heading are post-ganglionic fibres arising from the 
sympathetic and allied ganglia. 

The evidence centres round the action of adrenalin. Adrenalin was 
discovered comparatively recently,§ and it does not stand on the same footing 
as curari and nicotine, for from the first it has been a matter of discussion 
whether it acts on nerve endings or on muscle. Since it has long been 

* Bethe, c Allg. Anat. u. Physiol, d. Nervensystems ' (Leipzig), 1903. 

t Cosmettatos, 'Archives d'Ophthalmologie,' 1904. 

J Eve, ' Journ. of Physiol./ vol. 20, p. 334, 1896. 

§ Oliver and Schafer, ' Journ. of Physiol./ vol. 18, p. 230, 1895. 



190 Prof. J, N. Langley. On Nerve Endings and on [May 24, 

recognised that poisons act upon cells apart from nerve endings, the 
discussion on the action of adrenalin did not for a time raise the general 
questions we are considering here. 

Taking the facts so far as they are now ascertained,* it may be regarded 
as certain that the numerous effects produced by adrenalin are no whit 
impaired, and probably, indeed, are increased by degeneration of the 
sympathetic nerves which supply the structures on which it acts. On 
the assumption that the degeneration of the nerve endings is accompanied 
by degeneration of the nerve-fibres, this is clear evidence that adrenalin 
stimulates by acting directly on unstriated muscle and gland cells. 

The assumption is based on the fact that the nerve-fibres, on section, 
degenerate up to the peripheral plexus (or network). There is no obvious 
reason why the degeneration should not proceed throughout. Some cells, 
it is true, occur in close connection with the peripheral plexus, but it is 
practically certain that these are connective tissue cells. A few experiments 
have been made by Eletcherf on the nerve plexus in the retractor penis of 
the hedgehog. In these he found that the nerve plexus did not stain with 
methylene blue after degenerative section of the nerves supplying the 
muscle. 

But there are difficulties in accepting the conclusion that adrenalin does 
not act on nerve endings which are not met with or are met with to a much 
less extent in dealing with the effect of nicotine and curari upon striated 
muscle and nerve cells. The difficulties depend upon the apparently specific 
relation of adrenalin to the sympathetic system. The broad facts with 
regard to this relation are as follows : — 

Certain parts of the body are innervated by two systems of nerves, viz., 
by the sympathetic system and by either the cranial autonomic or the 
sacral autonomic system. It was pointed out by myselfj that the 
stimulating effects produced by adrenalin are in all cases (with the doubtful 
exception of the pupil in the dog)§ like those produced by stimulating the 
sympathetic, and not like those produced by stimulating either of the other 
systems. 

The sympathetic nerves cause contraction of nearly all the arteries of the 
body, but the contraction varies in ease of production and in intensity ; 

* Of. Lewandowsky, 'Arch. f. (Anat. u.) Physiol./ 1899, p. 360 ; Langley, ' Journ. of 
Physiol./ vol. 27, p. 237, 1901 ; Brodie and Dixon, ibid., vol. 30, p. 500, 1904 • Elliott, 
ibid., vol. 33, p. 401, 1905 ; Langley, ibid., vol. 33, p. 376, 1905. 

t Fletcher (' Proc. Physiol. Soc.,' p. xxxvi, 1897), ' Journ. of Physiol.,' vol. 22. 

J Langley, 'Journ. of Physiol.,' vol. 27, p. 237, 1901. 

§ The contraction of the pupil caused by adrenalin has been shown by Elliott (op. cit. 
supra) to be due to central stimulation. 



1906.] Special Excitable Substances in Cells. 191 

the effect of adrenalin is, in general, proportional to the effect of electrical 
excitation of the nerves. The arteries of the lungs, according to Brodie and 
Dixon,* and the coronary arteries, according to Schafer,f are equally unaffected 
by electrical stimulation of the sympathetic nerves and by adrenalin; the 
like absence of effect is found with many of the veins of the body. 

The sympathetic nerves supplying a given organ may produce different 
effects in different animals. In all these cases, so far as observed, the effect 
of adrenalin corresponds with the effect of the nerves. This has been shown 
in mammals chiefly by Elliott,^: and in amphibia and fish by Bottazzi.§ 

The differences which are found between the effects of adrenalin and of 
electrical stimulation of sympathetic nerves are, first, that in a tissue which 
receives both motor and inhibitory nerve-fibres from the sympathetic, the 
balance of motor and inhibitory effects are not necessarily the same with 
the two stimuli ; thus, in some cases adrenalin produces much greater and 
more lasting inhibition than can be caused by electrical nerve stimulation, 
and, secondly, that some tissues are readily affected by stimulation of the 
sympathetic nerves, and barely at all, or only in enormous doses, by 
adrenalin. 

Furthermore, it has been shown by I)ale|| and confirmatory evidence has 
been given by Elliott, that ergot abolishes all the constrictor effects of the 
sympathetic, without impairing any of the effects of the cranial or sacral 
autonomic nerves, or the inhibitory effects of the sympathetic. In this 
state adrenalin, according to Dale and to Elliott, causes inhibition in many 
of the regions innervated by the sympathetic, and has no constrictor effect 
whatever. Thus, for example, the bladder of the ferret normally contracts 
when either the sympathetic or the sacral nerves are stimulated, or when 
adrenalin is injected. After ergot the sacral nerves cause contraction as 
before, the sympathetic nerves and adrenalin cause inhibition. 

The special relationship of adrenalin to the sympathetic system is,primd 
facie, strongly supported by the close developmental connection of the supra- 
renal body with the sympathetic ganglia. This argument, however, loses 
some of its force in consequence of Dale's discovery that ergot, which is not 
formed at all in the body, has also a special action on the tissues innervated 
by the sympathetic system. 

* Op. cit. supra. 

t Schafer, ' Archives Intern, de Physiol.,' vol. 2, p. [141], 1904. 

% Elliot, op. cit. supra. 

§ Gf. Bottazzi and Costanzi, ' Nuove Kicerche sull' Azione dell' Adrenalina e d. Para- 
ganglina' (Napoli), 1905. 

|| Dale, 'Proc. Physiol. Soc.,' p. lviii ('Journ. of Physiol.,' vol. 32) and * Journ. of 
Physiol.,' vol. 34, in the press. 



192 Prof. J. N. Langley. On Nerve Endings and on [May 24, 

The difficulty, then, which we have to face is that of reconciling the fact 
that adrenalin has a special relation to tissues innervated by sympathetic 
nerves, with the deduction from the degeneration experiments that adrenalin 
does not act on the nerves or their endings. Elliott, adopting the theory 
that nerve and unstriated muscle are continuous, considers that adrenalin 
acts on the junction of the two — the my o-neural junction — and does not act 
either on muscle or on nerve endings. 

It is important to keep clearly in mind that the question whether 
adrenalin does or does not act on muscle or on nerve endings is, up to 
a certain point, a matter of nomenclature. 

If the nerve, the myo-neural junction, and the muscle, are regarded as 
successive parts of a continuous mass, it may then logically be said, on 
this theory, that adrenalin acts on the myo-neural junction and does not act 
on muscle or on nerve. But the conclusion depends upon the definition 
of muscle and of nerve. The junction, since it is not regarded as a separate 
entity comparable to the muscle cell or the nerve cell, must consist either 
of muscle substance or of nerve substance, or of both. That is to say, 
adrenalin must act either on muscle substance or on nerve substance, or 
on both. And as muscle substance is a part of the muscle cell, and a nerve 
substance is a part of the nerve cell, it cannot, from this point of view, be 
properly asserted either that adrenalin does not act on muscle, or that it 
does not act on nerve. The legitimate statement from the premises is that 
it does not act on any muscle substance or on any nerve substance outside 
the limits of the myoneural junction. 

Two arguments which have been used against the view that adrenalin acts on muscle 
should, I think, be definitely discarded. Dixon, Brodie and Dixon, and Elliott argue that 
since, after apocodeine, adrenalin does not stimulate certain unstriated muscle, and 
barium chloride does, adrenalin cannot act on muscle. This is the traditional argument 
used with regard to the effect of curari;on nerve endings in striated muscle. It rests on 
the identification of the contractile molecule of muscle with the whole muscle substance. 
It is not only conceivable that the irritable substance should be part of the sarcoplasm, 
but also that it might be a radicle of the contractile molecule. And in either case the 
irritable substance might be put out of action without destroying the contractile power 
of the muscle. 

Elliott argues also that it is unlikely that the blood vessels of the lungs or heart should 
differ in their intrinsic musculature from those of the intestine to such a biochemical 
degree that the one set should be slightly dilated by adrenalin and the other powerfully 
contracted. But, in fact, there is variation, and this can only be explained by a variation 
in nerves or muscles, and the variation might theoretically take place as well in the 
muscle as in the nerve. 

As regards the localisation of the receptive substance, strong evidence 
that this occurs to a considerable extent is afforded by the action both 



1906.] Special Excitable Substances in Cells. 193 

of adrenalin and of chrysotoxin on tissues which have a double nerve supply, 
but the evidence cannot be regarded as conclusive. 

In order to account for the special relation of adrenalin to the sympathetic 
system, Elliott supposes that the excitable substance of the myo-neural 
junction is formed in consequence of the union of the nerve with the muscle 
and not in virtue of any inherent property of the muscle. The central point 
of this theory is clearly applicable whether there is union or only contact of 
nerve and muscle, and there is much that is attractive in the view that 
the receptive substance owes its formation to the nerve, but it does not, 
I think, satisfactorily account for the different degree of action of adrenalin 
and chrysotoxin on the receptive substance in different cases,* nor for the 
persistence of the substance after nerve degeneration. If the receptive 
substance were formed in the muscle solely in consequence of its connection 
with a nerve, it seems most unlikely that the muscle would be able to take 
on the formation when the nerves have disappeared. 

The view I take is that the relation of poisons in general to special 
systems of nerves depends upon the developmental history of the connection 
of the different systems with the particular tissues. It seems to me certain 
that the various cells of the body have a constant tendency to vary in 
chemical composition, and it is probable that these variations in any one 
tissue are approximately the same at the same time.f It is fairly certain 
that different systems of nerves establish nervous connections with the cells 
at different periods of phylogenetic development, and it is probable that 
when nervous connection is made it tends to make permanent certain of the 
chemical conditions existing at the time. 

Thus the different systems of efferent nerves would chiefly, at any rate, 
owe their differences to the different characters of the " receptive " substances 
of the cells with which they have become connected.^ 

General Conclusions, 

In the foregoing account we have seen reason to believe that in each of 
the three great types of connection of the peripheral end of an efferent 
nerve with a cell it is some constituent of the cell substance which is 
stimulated or paralysed by poisons ordinarily taken as stimulating or para- 

* Of. Langley, 'Journ. of Physiol.,' vol. 33, p. 408, 1905. In this paper I have also 
considered the action of some other alkaloids which bear on the question, such as those of 
Anderson on the action of atropine, pilocarpine, and eserine on the denervated pupil. 

t A difference in the time of development of the sympathetic nerves to the skin and of 
those to the viscera might account for the different degree of action of poisons on the 
tissues innervated by the two sets of nerves. 

$ Some inferences from this theory I have given in the paper quoted above. 



194 Nerve Endings and Special Excitable Substances in Cells. 

lysing nerve endings. Reasons, though less complete, have been given for 
supposing that these poisons have no special action on nerve endings, and 
that physiologically the nerve ending is not essentiall} r different from the 
nerve-fibre. In that case not only the function of reacting to numerous 
chemical bodies, but probably also the special liability of both afferent and 
efferent nerves to fatigue must be transferred from the nerve endings to the 
same constituent of the cell. 

This theory adds to the complexity of the cell. It necessitates the 
presence in it of one or more substances (receptive substances) which are 
capable of receiving and transmitting stimuli, and capable of isolated 
paralysis, and also of a substance or substances concerned with the main 
function of the cell (contraction or secretion, or, in the case of nerve cells, of 
discharging nerve impulses). So far as this is concerned, it does but 
accentuate a view which has often been put forward and which indeed in 
some form or other is inseparable from the idea of protoplasm. 

I have spoken of different " substances " in the cell with the intent to use 
as vague a term as possible. The " substances/' I take it, are radicles of the 
protoplasmic molecule. At present, however, I do not think it advisable to 
speculate further either on this question or on certain other questions raised 
by the conclusions arrived at in the paper. There are a number of obvious 
experiments still to be made, and these, it may be hoped, will settle some of 
the problems, the solution of which is now but guess work. 











j^T^' 












1 









-Fowl, ana;sthelised with mt 
a V-shaped pi e(;e of wood, 
eyes are shut. 



.-phia and A.C.E. mixture, balanced on its thorax in 
The neck and legs hang down and are flaccid, the 




Fig. 2.— The same fowl as in fig. 1. Two minutes after injection of 5 milligrammes of 

nicotine into the jugular vein. The injection caused a gradual and fairly quick 
extension of the legs, retraction and twisting of the neck, and opening of the 
eyes. In order to show the eyes, the beak was held when taking the photo- 
graph. The fowl was unfastened throughout, and the injection caused no 
general movement nor any decrease of the anaesthesia. 







5£5jt&» 




L_-. ■* WSl 




4 




I^^3l^^^s 

















—The same fowl half an iiour after the injection of 5 milligrammes of nicotine. In 
the interval the fowl had been lifted up to observe the degree of contraction 
of the muscles, so that the position is probably not exactly the same as in the 
previous photograph. Most of the muscles stilt have some tone, more than 
they have in anesthesia without nicotine ; but the eye muscles are appa- 
rently in the normal anaesthetic state, for the eye is closed. The eye began to 
close in about a quarter of an hour. 




Fig. 6. — Nerve ending in sartorius muscle of frog three weeks after nerve section. 
Methylene blue stain. The tint of the several parts of the nerve ending in 
the figure represents roughly the degree of stain, but the tint of the bypo- 
leinmal fibres, and, to a less degree, that of the nuclei, is too deep. 




-Frog. Killed by destroying the whole of the central nervous system. Con- 
traction of the muscles of the fore limbs caused by nicotine.